Nucleoside analogues from push-pull functionalized branched-chain pyranosides

Article abstract of DOI:10.1515/znb-2006-0406

The reaction of methyl 4,6-O-benzylidene-2-deoxy-α-D-erythro- hexopyranosid-3-ulose (1) with ethynylmagnesium bromide in tetrahydrofuran and subsequent trimethylsilylation yielded the methyl 4,6-O-benzylidene-2-deoxy-3-C- ethynyl-3-O-trimethylsilyl-α-D-ri

Full text of DOI:10.1515/znb-2006-0406

Nucleoside Analogues from Push-Pull Functionalized Branched-Chain
Pyranosides*
Marcus Kordiana,b, Holger Feista, Willi Kantlehnerc, Manfred Michalikb, and
Klaus Pesekea
a Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, D-18051 Rostock
b Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a,
D-18059 Rostock
c Fachbereich Chemie, Fachhochschule Aalen, Beethovenstr. 1, D-73430 Aalen
Reprint requests to Prof. Dr. K. Peseke. Fax +49(381)4986412. E-mail:klaus.peseke@uni-rostock.de
Z. Naturforsch. 61b, 406 – 412 (2006); received January 6, 2006
The reaction of methyl 4,6-O-benzylidene-2-deoxy-α-D-erythro-hexopyranosid-3-ulose (1)
with ethynylmagnesium bromide in tetrahydrofuran and subsequent trimethylsilylation yielded
the methyl 4,6-O-benzylidene-2-deoxy-3-C-ethynyl-3-O-trimethylsilyl-α-D-ribo-hexopyranoside
(3). Push-pull functionalization of 3 with N,N,Nꢀ,Nꢀ,Nꢀꢀ,Nꢀꢀ-hexamethylguanidinium chloride
under basic conditions and following deprotection afforded the spiro{2,5-dihydro-3-dimethyl-
amino-furan-2,8’-4’,4’a,6’,7’,8’,8’a-hexahydro-6’-methoxy-2’-phenyl-pyrano[3,2-d][1.3]dioxine}-
5-ylidenemalononitrile (9). Furthermore, compound 1 reacted with N,N-dimethylformamide
dimethylacetal to furnish methyl (E)-4,6-O-benzylidene-2-deoxy-2-dimethylaminomethylene-α-D-
erythro-hexopyranosid-3-ulose (10). Treatment of 10 with methylhydrazine and amidines yielded
(4S,5aR,8R,9aS)-2,5a,6,9a-tetrahydro-4-methoxy-2-methyl-8-phenyl-4H-[1,3]dioxino[4’,5’:5,6]-
pyrano[4,3-c]pyrazole (11a) and (2R,4aR,6S,10bS)-4,4a,6,10b-tetrahydro-6-methoxy-2-phenyl-
[1,3]dioxino[4’,5’:5,6]pyrano[4,3-d]pyrimidines 12, respectively.
Key words: Deoxyuloses, Nucleoside Analogues, Pyrazoles, Pyrimidines, Enaminones
Introduction
describe the synthesis of furan, pyrimidine and pyra-
zole nucleoside analogues starting from D-glucose.
Anellated carbohydrates constitute a class of nucle-
oside analogues in which the noncarbohydrate hetero-
cycle is fused by one or two carbon atoms with the car-
bohydrate unit. Pyran rings are structural elements of
numerous natural products [1 – 3]. It has been found
that a great number of these compounds containing
anellated pyrans exhibit biological activity, for exam-
ple as cancerostatics or antibiotics [4 – 7]. Fused ring
systems with at least one pyran moiety are also very in-
teresting as potential inhibitors of glycosidases [8, 9].
Therefore, the development of new methods for the
synthesis of anellated pyranose derivatives has become
a topic of current interest in synthetic organic chem-
istry in the closer past [10 – 12].
Results and Discussion
The methyl 4,6-O-benzylidene-2-deoxy-α-D-ery-
thro-hexopyranosid-3-ulose (1) was synthesized
in six steps originating from D-glucose [15]. In a
Grignard reaction compound 1 was reacted with
ethynylmagnesium bromide to yield the methyl 4,6-
O-benzylidene-2-deoxy-3-C-ethynyl-α-D-ribo-hexo-
pyranoside (2) [16– 18]. The yield of the reaction
could not be increased over 70% because of a side
reaction of compound 1 with the Grignard reagent to
form ethyne. Treatment of the branched-chain mono-
saccharide 2 with trimethylsilyl chloride in pyridine
In recent years, we have reported the preparation of afforded the corresponding O-protected compound 3.
In the 1H NMR spectra of compound 2 the OH
singlet at δ = 3.46 and the 2’-H signal at δ = 2.45
were found as significant changes compared with the
1H NMR spectra of 1. The 13C NMR spectrum of 2
showed the signal for C-3 at δ = 65.9 which is shifted
upfield compared with the corresponding signal of
C-branched monosaccharides with push-pull function-
ality which could be used as precursors for the synthe-
sis of nucleoside derivatives [13, 14]. In this paper, we
* Presented in part at the 7th Conference on Iminium Salts
(ImSAT-7), Bartoloma¨/Ostalbkreis, September 6 – 8, 2005.
c
0932–0776 / 06 / 0400–0406 $ 06.00 ꢀ 2006 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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M. Kordian et al. · Nucleoside Analogues from Push-Pull Functionalized Branched-Chain Pyranosides
407
Scheme 1. Synthesis of methyl 4,6-O-benzylidene-2-deoxy-
3-C-ethynyl-α-D-ribo-hexopyranosides 2 and 3. (i) THF, 3 h,
22 ◦C; (ii) TMSCl, pyridine, 12 h, 22 ◦C.
Scheme 2. Synthesis of compounds 5 and 7. (i) NaH, THF,
3 h, 22 ◦C (5), 72 h, 55 ◦C (7); (ii) H2O, 0 ◦C; (iii) malonon-
itrile, THF, 24 h, 22 ◦C.
Fig. 1. NOE corelations of pyra-
noside 2.
ulose 1 (δ = 196.9). For the triple-bonded carbons
C-1’ and C-2’, signals were found at δ = 83.9 and
δ = 71.9, respectively.
The elucidation of the configuration at C-3 was pos-
sible by NOE spectroscopy. Thus, the two-dimensional
NOESY of 2 showed correlations of the OH hydro-
gen with the protons 5-H and 2eq-H which indicated
an (R)-configuration at C-3 (Fig. 1).
Scheme 3. Synthesis of compound 9. (i) KF, DMF, 24 h,
90 ◦C.
dimethylamine at the triple bond yields the pyranosidic
push-pull butadiene 7.
Following procedures of Kantlehner et al. [19– 21],
the synthesis of a push-pull butadiene from com-
pound 3 could be achieved by reaction of the terminal
ethynyl carbon with N,N,Nꢀ,Nꢀ,Nꢀꢀ,Nꢀꢀ-hexamethyl-
guanidinium chloride in tetrahydrofuran in the
presence of NaH (Scheme 2). Hydrolysis of the
intermediarily formed methyl 4,6-O-benzylidene-2-
deoxy-3-C-[3-tris(dimethylamino)propynyl]-3-O-tri-
methylsilyl-α-D-ribo-hexopyranoside (4) afforded
3-(methyl 4,6-O-benzylidene-2-deoxy-3-O-trimeth-
ylsilyl-a-D-ribo-hexopyranosid-3-C-yl)propynic acid
dimethylamide (5).
Contrary to these results, the in situ reaction of 4
with malononitrile gave 3-(E,Z)-2,4-bis(dimethylami-
no)-4-(methyl 4,6-O-benzylidene-2-deoxy-3-O-trime-
thylsilyl-α-D-ribo-hexopyranosid-3-C-yl)buta-1,3-di-
ene-1,1-dicarbonitrile (7). The mechanism of the re-
action could be described as follows: First an at-
tack of malononitrile at the C-3’ occurs with substi-
tution of two dimethylamino groups to furnish the di-
The 13C NMR spectrum of compound 7 showed the
signals for C-1’ and C-3’ at δ = 170.2 and δ = 169.2,
respectively. Furthermore, the signals of the dimethyl-
amino groups at δ = 41.8 and δ = 40.4 were found.
In a two-dimensional NOESY spectrum of 7 the pro-
ton H-2’ showed correlations with the protons H-4 and
both dimethylamino groups. Furthermore, correlations
were found between the signals of both dimethylamino
groups. From this result a twisted structure about the
bonds of the butadiene chain can be concluded.
Deprotection of the trimethylsilyl substituted 3-OH
group in ◦compound 7 with potassium fluoride in DMF
at −10 C [22] caused an intramolecular substitu-
tion of the dimethylamino group at C-3’ yielding the
spiroanellated compound 9 (Scheme 3). Therefore, the
isolation of the OH-group containing compound 8 was
not possible.
Absence of the typical signals of one of the di-
carbonitrile 6. A subsequent Michael-like addition of methylamino groups in the 1H and 13C NMR spec-
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M. Kordian et al. · Nucleoside Analogues from Push-Pull Functionalized Branched-Chain Pyranosides
rable reactions of α-aminomethyleneketones yielded
pyrimidines in high yields [25– 27]. The reaction
of push-pull functionalized ulose 10 with acetami-
dinium hydrochloride in N,N-dimethylformamide us-
ing potassium carbonate/18-crown-6 as base afforded
after chromatography compound 12a in a yield of 53%
(Scheme 4). The 13C NMR spectrum of 12a showed
a strong upfield shift for C-10a at δ = 160.7 (chem-
ical shift of the corresponding C-3 in compound 10
at δ = 187.5) and the absence of signals for the
dimethylamino and carbonyl group. These observa-
tions approved the cyclization through substitution of
the dimethylamino group and condensation with the
carbonyl group. In the 13C NMR spectrum of com-
pound 12a a signal of an N-methyl group was visible
at δ = 26.2. All other spectral data of this compound
were also in accordance with the quite similar structure
Scheme 4. Synthesis of compounds 11 and 12.
(i) HC(OMe)2NMe2, toluene, 12 h, 100 ◦C; (ii) NH2NHMe,
MeOH, 5 h, 22 ◦C; (iii) RC(NH2)=NH2+X− (12a: R = Me,
X− = Cl−; 12b: R = Ph, X− = Cl−; 12c: R = MeS,
X− = HSO4−), K2CO3, 18-crown-6, DMF, 17 h, −15 ◦C.
of 11a.
In the same way, the treatment of 10 with ben-
zamidinium chloride and methylisothiouronium sul-
fate in the presence of potassium carbonate/18-
crown-6 under reflux yielded the corresponding
[1,3]dioxino[4’,5’:5,6]pyrano[4,3-d]pyrimidines 12b
and 12c, respectively.
tra indicated the ring closing reaction. Moreover, the
downfield shift of the 4-H at δ = 5.33 (compared
with δ = 4.57 in compound 7) confirmed the cycliz-
ation.
Experimental Section
Reaction of hexopyranosidulose 1 with dimethyfor-
mamide dimethylacetal [14, 23, 24] afforded methyl
(E)-4,6-O-benzylidene-2-deoxy-2-dimethylaminome-
thylene-α-D-erythro-hexopyranosid-3-ulose (10) in
78% yield (Scheme 4). The specification of the E/Z-
isomerism in compound 10 was achieved by a NOESY
spectrum which showed cross peaks between the
protons of the dimethylamino group and the anomeric
proton. Therefore, the shown E-configuration can be
assumed (Scheme 4).
General procedures
Melting points were determined with a Boe¨tius melting
point apparatus and are corrected. Optical rotations were
measured with a Gyromat HP (Dr. Kernchen Ltd.) polarime-
ter. 1H and 13C NMR spectra were recorded with Bruker
spectrometers AC 250 (250.1 MHz and 62.9 MHz, respec-
tively) and ARX 300 (300.1 MHz and 75.5 MHz, respec-
tively). The calibration of spectra was carried out by means
of TMS (δH = 0) or solvent peaks (δH (CDCl3) = 7.25; δC
(CDCl3) = 77.0). For the assignment of H and 13C NMR
1
The hexopyranosid-3-ulose 10 reacted with methyl-
hydrazine in methanol at r. t. to furnish in a signals, DEPT and two-dimensional 1H,1H COSY and
NOESY as well as 1H,13C correlation spectra were recorded.
yield of 34% the pyrazoloanellated pyranoside 11a
(Scheme 4). In the 13C NMR spectrum of com-
Mass spectra were obtained with an AMD 402/3 spectrom-
eter (AMD Intectra GmbH). Elemental analyses were per-
pound 11a no signals for a carbonyl carbon atom
formed with a Leco CHNS-932. Column chromatography
and for the dimethylamino group were detected,
was carried out on silica gel 60 (0.063 – 0.20 mm, Merck).
thus confirming the expected cyclization. Because the
pyrano[4,3-c]pyrazole 11 could exist in two isomeric
forms 11a and 11b, NOESY experiments were carried
out. They showed cross peaks between the N-methyl
protons and 3-H, which corroborated the structure 11a
for the isolated product.
Thin-layer chromatography (TLC) was performed on silica
gel 60 GF254 foils (Merck) with detection by UV light and
by charring with sulfuric acid. HPLC chromatography was
carried out by a Merck SEPTECH apparatus and a column
(l = 250 mm, d = 25 mm) filled with Lichrosorb Si 60, 7 µm
(2 ml sample volume was used by a flow of 20 ml/min). Sol-
Furthermore, we improved the reaction of 10 with
vents and liquid reagents were purified and dried according
amidinium salts in the presence of a base. Compa- to recommended procedures.
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M. Kordian et al. · Nucleoside Analogues from Push-Pull Functionalized Branched-Chain Pyranosides
409
2
3
Methyl 4,6-O-benzylidene-2-deoxy-3-C-ethynyl-α-D-ribo- 1H, J2ax,2eq = 14.6 Hz, J1,2ax = 4.6 Hz, 2ax-H), 0.18 (s,
9H, Me3Si). – 13C NMR (62.9 MHz, CDCl3): δ = 137.7,
hexopyranoside (2)
128.8, 128.1, 126.3 (Ph), 101.8 (CHPh), 97.7 (C-1), 85.1
(C-1’), 83.0 (C-4), 72.8 (C-2’), 69.1 (C-6), 66.5 (C-3), 58.5
Methyl 4,6-O-benzylidene-2-deoxy-α-D-erythro-hexo-
pyranosid-3-ulose 1 (0.264 g, 1.0 mmol) was di◦ssolved
(C-5), 55.1 (MeO), 43.9 (C-2), 1.7 (Me3Si). – MS (EI):
in abs. tetrahydrofuran (15 ml) and cooled to 0 C. An
m/z(%) = 362 (22) [M+]. – C19H26O5Si (362.49): calcd.
ethynylmagnesium bromide solution in hexane (0.5 M, 4 ml)
was added and the mixture was stirred for 5 h (TLC control).
C 62.95, H 7.23; found C 62.49, H 7.12.
When the starting material had almost been consumed, the
reaction mixture was diluted with ethyl acetate (50 ml) and
water (20 ml). The now formed precipitate was filtered
using a glass filter filled with celite. The filter material was
3-(Methyl 4,6-O-benzylidene-2-deoxy-3-O-trimethylsilyl-α-
D-ribo-hexopyranosid-3-C-yl)propynic acid dimethylamide
(5)
To a solution of 3 (0.326 mg, 1 mmol) in abs. tetrahydro-
furan (10 ml) was added sodium hydride (0.05 g, 2.1 mmol)
at 22 ◦C. The resulting mixture was stirred under ar-
gon atmosphere. After 1 h of stirring N,N,Nꢀ,Nꢀ,Nꢀꢀ,Nꢀꢀ-
hexamethylguanidinium chloride (0.215 g, 1.2 mmol) were
added. The resulting solution was stirred for another 3 h and
after completion of the reaction (monitored by TLC) the mix-
ture was added to ice water (50 ml). The aqueous phase was
extracted with ethyl acetate (3 × 50 ml) and the combined
organic phases dried with sodium sulfate. Then the solvent
was evaporated in vacuo and the residue was purified by col-
umn chromatography (toluene/ethyl acetate 4 : 1) to obtain 5
washed three times with ethyl acetate. After separation of
the organic layer the aqueous phase was washed with ethyl
acetate (3 × 10 ml). The combined organic phases were
dried with sodium sulfate and evaporated in vacuo and the
remaining slightly yellow syrup was purified by column
chromatography (toluene/ethyl acetate 2 : 1) yielding 2 as
a colorless syrup. Yield 0.203 g (70%), colorless syrup. –
[α]2D2 = +48.4 (c 1.0, CHCl3). – Rf = 0.45 (toluene/ethyl
acetate 2 : 1). – 1H NMR (250 MHz, CDCl3): δ = 7.55 – 7.51
(m, 2H, Ph), 7.37 – 7.33 (m, 3H, Ph), 5.66 (s, 1H, CHPh),
4.77 (dd, 1H, 3J1,2ax = 4.3 Hz, 3J1,2eq = 1.0 Hz, 1-H), 4.32
(dd, 1H, 2J6ax,6eq = 10.0 Hz, 3J5,6eq = 5.0 Hz, 6eq-H), 4.16
(dt, 1H, 3J5,6ax = 10.0 Hz, 3J4,5 = 9.5 Hz, 3J5,6eq = 5.0 Hz,
5-H), 3.77 (t, 1H, 2J6ax,6eq = 3J5,6ax = 10.0 Hz, 6ax-H), 3.70
(d, 1H, 3J4,5 = 9.5 Hz, 4-H), 3.46 (s, 1H, OH), 3.39 (s, 3H,
MeO), 2.45 (s, 1H, 2’-H), 2.37 (dd, 1H, 2J2ax,2eq = 15.0 Hz,
3J1,2eq = 1.0 Hz, 2eq-H), 2.20 (dd, 1H, 2J2ax,2eq = 15.0 Hz,
3J1,2ax = 4.3 Hz, 2ax-H). – 13C NMR (62.9 MHz, CDCl3):
δ = 137.1, 129.0, 128.2, 126.2 (Ph), 102.0 (CHPh), 97.8
(C-1), 83.9 (C-1’), 82.1 (C-4), 71.9 (C-2’), 68.9 (C-6),
65.9 (C-3), 59.1 (C-5), 55.5 (MeO), 41.4 (C-2). – MS (EI):
m/z(%) = 290 (1) [M+]. – C16H18O5 (290.31): calcd.
C 66.19, H 6.25; found C 65.50, H 6.43.
◦
as a white solid. Yield 0.337 g (78%). – m. p. 194 C. –
[α]2D2 = +42.9 (c 1.0, CHCl3). – Rf = 0.52 (toluene/ethyl
acetate 4 : 1). – IR (capillary): ν = 2226 (C≡C), 1641.3
1
(C=O) (cm−1). – H NMR (250 MHz, CDCl3): δ = 7.50 –
7.45 (m, 2H, Ph), 7.37 – 7.30 (m, 3H, Ph), 5.60 (s, 1H,
3
CHPh), 4.70 (br d, 1H, J1,2ax = 4.7 Hz, 1-H), 4.32 – 4.18
(m, 2H, 5-H, 6eq-H), 3.76 – 3.59 (m, 2H, 4-H, 6ax-H), 3.31
(s, 3H, MeO), 3.12 (s, 3H, Me2N), 2.93 (s, 3H, Me2N),
2.35 (dd, 1H, 2J2ax,2eq = 14.5 Hz, 3J1,2eq = 0.8 Hz, 2eq-H),
2.14 (dd, 1H, 2J2ax,2eq = 14.5 Hz, 3J1,2ax = 4.7 Hz, 2ax-H),
0.18 (s, 9H, Me3Si). – 13C NMR (62.9 MHz, CDCl3): δ =
153.8 (C-3’), 137.5, 128.8, 128.0, 126.1 (Ph), 101.7 CHPh,
97.5 (C-1), 91.3 (C-2’), 82.8 (C-4), 77.0 (C-1’), 69.1 (C-6),
67.0 (C-3), 58.3 (C-5), 55.1 (MeO), 43.0 (C-2), 38.1, 34.0
(Me2N), 1.6 (Me3Si). – MS (EI): m/z(%) = 433 (4) [M+].
– C22H31NO6Si (433.57): calcd. C 60.94, H 7.21, N 3.23;
found C 61.49, H 7.23, N 2.61.
Methyl 4,6-O-benzylidene-2-deoxy-3-C-ethynyl-3-O-trime-
thylsilyl-α-D-ribo-hexopyranoside (3)
Compound 2 (0.29 g, 1.0 mmol) and trimethylsilyl chlo-
ride (0.12 ml, 1.0 mmol) in pyridine (10 ml) were stirred
at 22 ◦C for 12 h. After completion of the reaction (monitored
by TLC) the solvent was evaporated in vacuo and the residue
was purified by column chromatography (toluene/ethyl ac-
etate 2 : 1) to furnish a viscous compound 3: Yield 0.260 g
(72%), colorless syrup. – [α]2D2 = +42.2 (c 1.0, CHCl3). –
Rf = 0.7 (toluene/ethyl acetate 2 : 1). – 1H NMR (250 MHz,
CDCl3): δ = 7.54 – 7.51 (m, 2H), 7.38 – 7.33 (m, 3H, Ph),
3-(E,Z)-2,4-Bis(dimethylamino)-4-(methyl-4,6-O-benzyl-
idene-2-deoxy-3-O-trimethylsilyl-α-D-ribo-hexopyranosid-
3-C-yl)buta-1,3-diene-1,1-dicarbonitrile (7)
To a suspension of 3 (0.362 g, 1.0 mmol) and sodium hy-
dride (0.05 g, 2.1 mmol) in abs. tetrahydrofuran (10 ml) was
added N,N,Nꢀ,Nꢀ,Nꢀꢀ,Nꢀꢀ-hexamethylguanidinium chloride
3
◦
5.61 (s, 1H, CHPh), 4.69 (br d, 1H, J1,2ax = 4.6 Hz, 1-H),
(0.215 g, 1.2 mmol) at 22 C. The resulting mixture was
2
stirred for 72 h at 55 ◦C. After cooling to 22 ◦C a suspension
4.30 – 4.20 (m, 2H, 5-H, 6eq-H), 3.70 (t, 1H, J6ax,6eq
=
3J5,6ax = 10.0 Hz, 6ax-H), 3.58 (d, 1H, J4,5 = 9.2 Hz, of malononitrile (0.066 g, 1.0 mmol) and sodium hydride
3
4-H), 3.31 (s, 3H, MeO), 2.45 (s, 1H, 2’-H), 2.30 (dd, 1H, (0.05 mg, 1.25 mmol) in abs. tetrahydrofuran (5 ml) were
3
2J2ax,2eq = 14.6 Hz, J1,2eq = 0.8 Hz, 2eq-H), 2.10 (dd, added. The resulting mixture was stirred for another 24 h
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M. Kordian et al. · Nucleoside Analogues from Push-Pull Functionalized Branched-Chain Pyranosides
◦
at 22 C. After completing of the reaction (monitored by itored ◦by TLC) compound 10 precipitated during cooling
TLC) methanol was added, the solvent was evaporated in to 22 C. The product was filtered and recrystallized from
vacuo, and the residue was purified by column chromatog- ethanol. Yield 170 mg (78%), yellow needles. – m. p. 148 –
◦
raphy (ethyl acetate) to yield compound 7. Yield 0.142 g 152 C. – [α]2D2 = +196.9 (c = 1.0, CHCl3). – Rf = 0.1
(27%), Yellow solid; m. p. 227 ◦C. – Rf = 0.2 (ethyl acetate).
(toluene/ethyl acetate 1 : 2). – 1H NMR (250 MHz, CDCl3):
– 1H NMR (250 MHz, CDCl3): δ = 7.49 – 7.47 (m, 2H, Ph), δ = 7.61 (s, 1H, 1’-H), 7.52 – 7.50 (m, 2H, Ph), 7.34 – 7.29
7.35 – 7.32 (m, 3H, Ph), 5.64 (s, 1H, CHPh), 4.68 (br d, 1H, (m, 3H. Ph), 5.56 (s, 1H, 1-H), 5.60 (s, 1H, CHPh), 4.32
3J1,2ax = 4.2 Hz, 1-H), 4.57 (s, 1H, 2’-H), 4.40 – 4.34 (m, (dd, 1H, 2J6ax,6eq = 10.1 Hz, 3J5,6eq = 5.1 Hz, 6eq-H), 4.24
3
3
3
(dt, 1H, J4,5
=
3J5,6ax = 10.1 Hz, J5,6eq = 5.0 Hz, 5-H),
2H, 5-H, 6eq-H), 4.25 (d, 1H, J4,5 = 9.0 Hz, 4-H), 3.73
3
2
(m, 1H, 6ax-H), 3.34 (s, 3H, MeO), 3.04 (s, 6H, Me2N),
2.96 (s, 6H, Me2N), 2.85 (dd, 1H, J2ax,2eq = 14.4 Hz,
4.02 (d, 1H, J4,5 = 10.1 Hz, 4-H), 3.77 (t, 1H, J6ax,6eq
=
2
3J5,6ax = 10.1, 6ax-H), 3.38 (s, 3H, MeO), 3.11 (s, 6H,
Me2N). – 13C NMR (62.9 MHz, CDCl3): δ = 187.5 (C-3),
151.9 (C-1’), 137.2, 129.0, 128.1, 126.6 (Ph), 102.5 (CHPh),
102.2 (C-2), 97.9 (C-1), 79.2 (C-4), 69.3 (C-6), 61.6 (C-5),
53.3 (MeO), 44.0 (br, NMe2). – MS (EI): m/z(%) = 319
(28) [M+]. – C17H21NO5 (319.14): calcd. C 63.94, H 6.63,
N 4.39; found C 62.81, H 6.52, N 4.16.
3J1,2eq = 0.6 Hz, 2eq-H), 1.64 (dd, 1H, 2J2ax,2eq = 14.4 Hz,
3J1,2ax = 4.6 Hz, 2ax-H), 0.16 (s, 9H, Me3Si). – 13C NMR
(62.9 MHz, CDCl3): δ = 170.2, 169.2 (C-1’, C-3’), 137.1,
129.0, 128.2, 126.2 (Ph), 120.8 (2 CN), 102.1 (CHPh), 98.0
(C-1), 88.4 (C-2’), 80.0 (C-4), 76.5 (C-4’), 69.7 (C-6), 58.4
(C-5), 55.1 (MeO), 48.1 (C-3), 40.3 (C-2), 41.8 (Me2N), 40.4
(Me2N), 2.3 (Me3Si). – MS (EI): m/z(%) = 526 (69) [M+].
– C27H38N4O5Si (385.417): calcd. C 61.57, H 7.27, N 10.64;
found C 61.48, H 7.30, N 10.14.
(4S,5aR,8R,9aS)-2,5a,6,9a-Tetrahydro-4-methoxy-2-methyl-
8-phenyl-4H-[1,3]dioxino[4’,5’:5,6]pyrano[4,3-c]pyrazole
(11a)
Spiro{2,5-dihydro-3-dimethylamino-furan-2,8’-4’,4’a,6’,7’,
8’,8’a-hexahydro-6’-methoxy-2’-phenyl-pyrano[3,2-d]-
[1.3]dioxine}-5-ylidenemalononitrile (9)
To a solution of compound 10 (0.096 g, 0.3 mmol)
in methanol (5 ml) was added methylhydrazine (0.014 g,
◦
0.3 mmol). The mixture was stirred for 5 h at 22 C. Af-
ter completion of the reaction the solvent was removed in
vacuo and the residue purified by column chromatography
(toluene/ethyl acetate 1 : 1) to obtain 11a as yellow syrup.
Yield 0.039 g (43%). – [α]2D2 = +34.8 (c = 1.0, CHCl3). –
Rf = 0.4 (toluene/ethyl acetate 1 : 1). – 1H NMR (250 MHz,
CDCl3): δ = 7.55 – 7.52 (m, 2H, Ph), 7.35 – 7.30 (m, 3H,
Ph), 7.23 (s, 1H, 3-H), 5.74 (s, 1H, 8-H), 5.55 (s, 1H, 4-H),
Compound 7 (0.052 g, 0.1 mmol) was dissolved in abs.
dimethylformamide (3 ml). After the addition of potassium
fluoride (0.0083 g, 0.14 mmol) the mixture was stirred
for 24 h at 90 ◦C. Removing of the solvent in vacuo yielded
the row material which was purified by column chromatog-
raphy (ethyl acetate). Yield 0.023 mg (78%), yellow syrup.
– [α]2D2 = −31.3 (c 0.9, CHCl3). – Rf = 0.5 (ethyl ac-
etate). – 1H NMR (250 MHz, CDCl3): d = 7.35 (br, 5H,
4.76 (d, 1H, 3J5a,9a = 9.2 Hz, 9a-H), 4.38 (dd, 1H, 2J6ax,6eq
10.2 Hz, 3J5a,6eq = 4.6 Hz, 6eq-H), 4.13 (ddd, 1H, 3J5a,6ax
=
=
Ph), 5.63 (s, 1H, 2’-H), 5.33 (s, 1H, 4-H), 4.86 (br d, 1H,
3
10.4, 3J5a,9a = 9.2 Hz, 3J5a,6eq = 4.6 Hz, 5a-H), 3.96 (t, 1H,
ꢀ
ꢀ
J6 ,7 = 4.6 Hz, 6’-H), 4.38 – 4.19 (m, 3H, 4’eq-H, 4’a-H,
8’a-H), 3.82 (t, 1H, 2J4 ax,4 eq = 3J4 ax,4 a = 10.0 Hz, 4’ax-H),
3
2J6ax,6eq = 10.2, J5a,6ax = 10.4 Hz, 6ax-H), 3.86 (s, 3H,
ꢀ
ꢀ
ꢀ
ꢀ
MeN), 3.50 (s, 3H, MeO). – 13C NMR (62.9 MHz, CDCl3):
δ = 146.3 (C-9b), 137.3, 129.2, 128.2, 126.8 (Ph), 127.9
(C-3), 115.9 (C-3a), 102.5 (C-8), 96.0 (C-4), 75.1 (C-9a),
69.5 (C-6), 64.6 (C-5a), 55.6 (MeO), 39.2 (Me). – MS (EI):
m/z(%) = 302 (0.4) [M+]. – C16H18N2O4 (302.33): calcd.
C 63.56, H 6.00, N 9.27; found C 63.43, H 5.97, N 9.13.
3.38 (s, 3H, MeO), 3.17 (s, 3H), 3.05 (s, 3H) (Me2N), 2.83
2
3
ꢀ
ꢀ
ꢀ
ꢀ
(dd, 1H, J7 ax,7 eq = 15.2 Hz, J6 ,7 = 4.6 Hz), 2.03 (d,
1H, J7 ax,7 eq = 15.2 Hz) (7’ax-H, 7’eq-H). – 13C NMR
(62.9 MHz, CDCl3): d = 172.4, 170.5 (C-3, C-5), 136.9,
129.0, 128.1, 126.0 (Ph), 117.7, 117.3 (2 CN), 101.6 (C-2’),
97.0 (C-6’), 91.8 (C-8’), 86.5 (C-4), 76.5 (C-8’a), 69.0
(C-4’), 60.0 (C-4’a), 55.4 (MeO), 38.9, 37.3 (Me2N), 37.4
(C-7’). – MS (EI): m/z(%) = 409 (100) [M+] – HRMS
C22H23N3O5 (409.44): calcd. 409.16377; found 409.16279.
2
ꢀ
ꢀ
(2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-9-
methyl-2-phenyl[1,3]dioxino[4’,5’:5,6]pyrano[4,3-d]-
pyrimidine (12a)
Methyl (E)-4,6-O-benzylidene-2-deoxy-2-dimethylamino-
methylene-a-D-erythro-hexopyranosid-3-ulose (10)
A
suspension of potassium carbonate (0.260 g,
1.88 mmol), 18-crown-6 (0.450 g, 1.70 mmol) and
To a solution of 1 (0.264 g, 1.0 mmol) in abs. toluene acetamidinium chloride (0.060 g, 0.6 mmol) i◦n abs. N,N-di-
(10 ml) was added N,N-dimethylformamide dimethylac- methylformamide (3 ml) was stirred at −15 C for 20 min.
etal (2.5 ml, 18.9 mmol). The resulting mixture was heated Compound 10 (0.1 g, 0.3 mmol) was added to the solu-
◦
for 12 h at 100 C. After completion of the reaction (mon- tion. The reaction mixture was stirred for another 17 h
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411
at −15 ◦C and then water (200 ml) was added to the solution. 4eq-H), 4.15 (ddd, 1H, 3J4a,4ax = 10.3 Hz, 3J4a,10b = 9.5 Hz,
2
3
The resulting mixture was extracted with dichloromethane 3J4a,4eq = 4.9 Hz, 4a-H), 3.98 (t, 1H, J4ax,4eq = J4ax,4a
=
10.3 Hz, 4ax-H), 3.60 (s, 3H, MeO). – 13C NMR (62.9 MHz,
CDCl3): δ = 164.8 (C-9), 161.0 (C-10a), 156.6 (C-7), 137.1,
137.0, 131.0, 129.1, 128.6, 128.5, 128.3, 126.4 (Ph), 124.7
(C-6a), 102.4 (C-2), 96.5 (C-6), 76.0 (10b), 69.3 (C-4), 63.0
(C-4a), 56.2 (MeO). – MS (EI): m/z(%) = 376 (22) [M+]. –
C22H20N2O4 (376.41): calcd. C 70.20, H 5.36, N 7.44; found
C 70.16, H 5.30, N 7.39.
(4×40 ml) and the combined organic phases were dried over
sodium sulfate. After filtration the solvent was evaporated
in vacuo. The residue was dissolved in methanol and silica
gel was added. After stirring for 10 min the solvent was
removed under reduced pressure and the silica based residue
was purified by column chromatography (toluene/ethyl
acetate 1 : 1). Yield 0.015 g (53%), yellow crystals. –
[α]2D5 = +64.7 (c = 0.8, CHCl3). – Rf = 0.2 (toluene/ethyl
acetate 1 : 1). – 1H NMR (250 MHz, CDCl3): δ = 8.54
(s, 1H, 7-H), 7.57 – 7.53 (m, 2H, Ph), 7.39 – 7.34 (m, 3H,
Ph), 5.76 (s, 1H, 2-H), 5.54 (s, 1H, 6-H), 4.66 (d, 1H,
3J4a,10b = 9.5 Hz, 10b-H), 4.43 (dd, 1H, 2J4ax,4eq = 10.4 Hz,
3J4eq,4a = 4.9 Hz, 4eq-H), 4.17 (ddd, 1H, 3J4ax,4a = 10.4 Hz,
(2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-9-
methylsulfanyl-2-phenyl[1,3]dioxino[4’,5’:5,6]pyrano–
[4,3-d]pyrimidine (12c)
Following the procedure for 12a, compound 10 (0.032 g,
0.1 mmol) and S-methylisothiouronium sulfate (0.04 g,
0.21 mmol) were allowed to react. Yield 0.011 g (31%),
3
3J4a,10b = 9.5 Hz, J4eq,4a = 4.9 Hz, 4a-H), 3.94 (t, 1H,
2J4ax,4eq =3 J4ax,4a = 10.4 Hz, 4ax-H), 3.58 (s, 3H, MeO),
2.76 (s, 3H, Me). – 13C NMR (250 MHz, CDCl3): δ = 168.8
(C-9), 160.7 (C-10a), 156.4 (C-7), 136.9, 129.3, 128.3, 126.7
(Ph), 124.2 (C-6a), 102.9 (C-2), 96.5 (C-6), 75.9 (C-10b),
69.3 (C-4), 63.0 (C-4a), 56.2 (MeO), 26.2 (Me). – MS (EI):
m/z(%) = 314 (14) [M+]. – C17H18N2O4 (314.34): calcd.
C 64.96, H 5.77, N 8.91; found C 64.61, H 5.67, N 8.01.
◦
white needles. – m. p. 235 C. – [α]2D3 = −19.6 (c = 1.0,
CHCl3). – Rf = 0.6 (heptane/ethyl acetate 1 : 1). – 1H NMR
(250 MHz, CDCl3): δ = 8.40 (s, 1H, 7-H), 7.58 – 7.53 (m,
2H, Ph), 7.39 – 7.35 (m, 3H, Ph), 5.74 (s, 1H, 2-H), 5.51
3
(s, 1H, 6-H), 4.62 (d, 1H, J4a,10b = 9.5 Hz, 10b-H), 4.43
2
3
(dd, 1H, J4ax,4eq = 10.3 Hz, J4eq,4a = 4.9 Hz, 4eq-H),
3
3
4.13 (ddd, 1H, J4ax,4a = 10.3 Hz, J4a,10b = 9.5 Hz,
3J4eq,4a = 4.9 Hz, 4a-H), 3.93 (t, 1H, J4ax,4eq = J4ax,4a
10.3 Hz, 4ax-H), 3.56 (s, 3H, MeO), 2.56 (s, 3H, MeS).
13C NMR (62.9 MHz, CDCl3): δ = 173.5 (C-9), 160.9
=
2
3
(2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-2,9-di-
phenyl[1,3]dioxino[4’,5’:5,6]pyrano[4,3-d]pyrimidine
(12b)
–
(C-10a), 156.4 (C-7), 136.9, 129.2, 128.2, 126.4 (Ph), 122.1
(C-6a), 102.4 (C-2), 96.6 (C-6), 75.8 (C-10b), 69.2 (C-4),
62.8 (C-4a), 56.1 (MeO), 14.2 (MeS). – MS (EI): m/z(%) =
346 (0.5) [M+]. – C17H18N2O4S (346.40): calcd. C 58.94,
H 5.24, N 8.09, S 9.26; found C 58.13, H 4.97, N 7.76,
S 8.67.
Compound 10 (0.032 g, 0.1 mmol) and benzamidinium
chloride (0.04 g, 2.5 mmol) were converted as described
for 12a. Yield 0.024 g (66%), yellow powder. – m. p. 115 –
119 ◦C. – [α]2D4 = +94.4 (c = 0.9, CHCl3). – Rf = 0.2
(toluene/ethyl acetate 1 : 1). – 1H NMR (250 MHz, CDCl3):
δ = 8.69 (s, 1H, 7-H), 8.50 – 8.43 (m, 2H, Ph), 7.65 –
7.61 (m, 2H, Ph), 7.49 – 7.38 (m, 3H, Ph), 5.81 (s, 1H,
Acknowledgement
3
We thank the Fonds der Chemischen Industrie for finan-
2-H), 5.59 (s, 1H, 6-H), 4.73 (d, 1H, J4a,10b = 9.5 Hz,
10b-H), 4.47 (dd, 1H, 2J4ax,4eq = 10.3 Hz, 3J4eq,4a = 4.9 Hz, cial support.
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